Introduction to the Reports from the Insights in Pediatric CAR T-cell Immunotherapy: Recent Advances and Future Directions (INSPIRED) Symposium

The tremendous success of chimeric antigen receptor (CAR) T-cells in children and young adults (CAYA) with relapsed/refractory B-cell acute lymphoblastic leukemia is tempered by toxicities such as cytokine release syndrome (CRS). Despite expansive information about CRS, profiling of specific end-organ toxicities secondary to CAR T-cell therapy in CAYAs is limited. This retrospective, single-center study sought to characterize end-organ specific adverse events (AEs) experienced by CAYAs during the first 30 days following CAR T-cell infusion. AEs graded using Common Terminology Criteria for Adverse Events (CTCAE) were collected on 134 patients enrolled on one of three phase 1 CAR T-cell trials (NCT01593696, NCT02315612, and NCT03448393), targeting CD19 and/or CD22. A total of 133 (99.3%) patients experienced at least 1 > grade 3 (Gr3) AE across 17 organ systems, 75 (4.4%) of which were considered dose or treatment limiting toxicities. Excluding cytopenias, 109 (81.3%) patients experienced a median of 3 >Gr3 non-cytopenia (NC) AEs. The incidence of >Gr3 NC AEs was associated with development (p <0.0001) and severity (p=0.0002) of CRS as well as pre-infusion disease burden (> 25% marrow blasts; p <0.0001). While those with complete remission trended toward experiencing more >Gr3 NC AEs than non-responders, (median 4 versus 3, p=0.10), non-responders experiencing CRS (n=17, 37.8%) had the highest degree of NC AEs across all patients (median 7 versus 4 in responders experiencing CRS, p=0.07). Greater understanding of these toxicities and the ability to predict which patients may experience more toxicities is critical as the array of CAR T-cell therapies expand. Clinical Trial # NCT01593696, NCT03448393.